Chapter 200

## Abstract

1. Disorders of free sialic acid storage are characterized by either lysosomal or cytoplasmic accumulation of the negatively charged monosaccharide, sialic acid (N-acetylneuraminic acid). The lysosomal free sialic acid storage diseases, Salla disease and infantile free sialic acid storage disease (ISSD), are autosomal recessively inherited disorders with various degrees of psychomotor retardation. Both Salla disease and ISSD result from accumulation of free sialic acid in lysosomes due to an impaired carrier-mediated transport system in the lysosomal membrane. They are allelic disorders of a gene assigned to the proximal portion of the long arm of chromosome 6. The gene was recently cloned and mutations in both phenotypes were identified. The transport system also recognizes other acidic monosaccharides, but structural characteristics of the transport protein are still unknown. The single cytoplasmic free sialic acid storage disease is sialuria, due to impaired feedback inhibition of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase by cytidine monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac). Its gene was recently cloned.

2. The free sialic acid storage disorders include Salla disease and the more severe infantile free sialic acid storage disease, ISSD. Patients with Salla disease, a disorder largely of the Finnish population, are normal at birth, but develop psychomotor delay and ataxia in infancy. Intelligence is moderately to severely impaired, and life span is slightly reduced. In contrast, patients with ISSD can present at birth and often succumb in the first year of life. They have failure to thrive, hepatosplenomegaly, severe mental and motor retardation, and they often have coarse facial features and dysostosis multiplex. Intermediate phenotypes have been reported. Dysmyelination of the brain is a constant and crucial finding in all types of lysosomal free sialic acid storage disorders, as documented by magnetic resonance imaging. There are over 120 Salla disease patients known, mostly with Finnish background, and more than 27 ISSD cases reported.

3. Patients with Salla disease and ISSD store, respectively, approximately 10 times and 100 times the normal amounts of free (unbound) N-acetylneuraminic acid in their tissues, and excrete 10 and 100 times normal amounts in the urine. Glucuronic acid also accumulates in cultured fibroblasts of patients with Salla disease and ISSD, because the lysosomal monosaccharide carrier defective in these disorders recognizes, in addition to sialic acid, glucuronic acid and other acidic monosaccharides.

4. The lysosomal free sialic acid storage disorders can be diagnosed based on increased urinary free sialic acid and histologic and electron microscope evidence of lysosomal storage on skin or conjunctival biopsy. Mutation assay can be applied in the Finnish population because of the high prevalence of the founder mutation. Prenatal diagnosis is based on sialic acid assay of a chorionic villus biopsy or, alternatively, using molecular studies, either genetic linkage analysis or mutation assay. Carriers can be identified in those families or populations in which the disease-causing mutation is known.

5. Sialuria, reported in only four patients, is characterized by hepatosplenomegaly, coarse facial features, and various degrees of developmental delay. The symptoms do not appear to progress. The disorder is diagnosed by the finding of gram quantities of free sialic acid in a 24-h urine, and vastly increased concentrations of free sialic acid in the cytoplasm of cultured fibroblasts. The basic defect consists of failure to regulate sialic acid synthesis, due to impaired feedback inhibition of UDP-GlcNAc 2-epimerase by CMP-Neu5Ac. The human epimerase gene has been sequenced, and three sialuria mutations identified; these indicate the region of the enzyme that binds CMP-Neu5Ac. Sialuria appears to be an autosomal dominant disorder. Only symptomatic therapy is available.

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